Granted Patent
B2
US 12,544,371 · App. 17/906,229 · Granted Feb 10, 2026
Methods and compositions for treating acute lung injury and acute respiratory distress syndrome
Inventors:
Kenneth A. Stauderman (La Jolla, CA); Michael Dunn (La Jolla, CA); Sudarshan Hebbar (La Jolla, CA); Rachel Leheny (La Jolla, CA)
Assignee:
CalciMedica, Inc.
View Patent ↗
Loading inventors, assignments & file history…
Abstract
Compositions and methods related to the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) including viral pneumonia through the pharmaceutical manipulation of calcium signaling are disclosed. Such compositions and methods may be used to reduce pro-inflammatory cytokine releases that may lead to ALI and/or ARDS.
Claims (20)
1 . A method for treating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) in a subject comprising administering a therapeutically effective amount of an intracellular Calcium signaling inhibitor to said subject.
2 . The method of claim 1 , wherein the ALI or ARDS comprises pneumonia.
3 . The method of claim 2 , wherein the pneumonia comprises a viral pneumonia.
4 . The method of claim 3 , wherein the viral pneumonia comprises a viral pneumonia due to a coronavirus, an adenovirus, an influenza virus, a rhinovirus, or a respiratory syncytial virus.
5 . The method of claim 4 , wherein the viral pneumonia comprises a viral pneumonia due to a coronavirus.
6 . The method of claim 5 , wherein the coronavirus is SARS-COV, SARS-COV-2, or MERS-COV.
7 . The method of claim 6 , wherein the coronavirus is SARS-COV-2.
8 . The method of claim 3 , wherein the viral pneumonia comprises a viral pneumonia due to an influenza virus.
9 . The method of claim 8 , wherein the influenza virus comprises influenza A, influenza B, influenza C, or influenza D.
10 . The method of claim 1 , wherein the ALI or ARDS is caused by a ventilator.
11 . The method of claim 1 , subsequent to said administering a therapeutically effective amount of an intracellular Calcium signaling inhibitor, an expression level or circulating level of a cytokine is decreased from a baseline level in said subject.
12 . The method of claim 11 , wherein said cytokine is selected from the group consisting of IL-2, IL-6, IL-7, IL-17, TNF-α, IFN-α, IFN-β, IFN-ω, and IFN-γ.
13 . The method of claim 1 , subsequent to said administering a therapeutically effective amount of an intracellular Calcium signaling inhibitor, an expression level or circulating level of D-dimer is decreased from a baseline level in said subject.
14 . The method of claim 1 , wherein said intracellular Calcium signaling inhibitor is a compound having the structure of: N-(5-(6-ethoxy-4-methylpyridin-3-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(2-ethyl-6-methylbenzo[d]oxazol-5-yl)pyridin-2-yl)-3,5-difluoroisonicotinamide, N-(4-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)phenyl)-2-fluorobenzamide, N-(5-(1-ethyl-3-(triflouromethyl)-1H-pyrazol-5-yl)pyrazin-2-yl)-2,4,6-trifluorobenzamide, 4-chloro-1-methyl-N-(4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1H-pyrazole-5-carboxamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,6-difluorobenzamide, N-(4-(3-(difluoromethyl)-5-methyl-1H-pyrazol-1-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, N-(4-(3-(difluoromethyl)-1-methyl-1H-pyrazol-5-yl)-3-fluorophenyl)-2,4,6-trifluorobenzamide, 4-chloro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)-1-methyl-1H-pyrazole-5-carboxamide, 3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-((3-methylisothiazol-4-yl)methyl)aniline, N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide, N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine, 3,5-difluoro-N-(3-fluoro-4-(3-methyl-1-(thiazol-2-yl)-1H-pyrazol-4-yl)phenyl)isonicotinamide, 5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-N-(2,4,6-trifluorobenzyl)pyridin-2-amine, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,4,6-trifluorobenzamide, N-(5-(5-chloro-2-methylbenzo[d]oxazol-6-yl)pyrazin-2-yl)-2,6-difluorobenzamide, N-(5-(6-ethoxy-4-methylpyridin-3-yl)thiazol-2-yl)-2,3,6-trifluorobenzamide, N-(5-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)-2,3,6-trifluorobenzamide, 2,3,6-trifluoro-N-(3-fluoro-4-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)benzamide, 2,6-difluoro-N-(4-(5-methyl-2-(trifluoromethyl)oxazol-4-yl)phenyl)benzamide, or N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
15 . The method of claim 14 , wherein said intracellular Calcium signaling inhibitor is a compound of chemical name N-(5-(6-Chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
16 . The method of claim 14 , wherein said intracellular Calcium signaling inhibitor is a compound of chemical name N-(2,6-difluorobenzyl)-5-(1-ethyl-3-(thiazol-2-yl)-1H-pyrazol-5-yl)pyrimidin-2-amine or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
17 . A composition comprising an intracellular Calcium signaling inhibitor and at least a compound for treating ALI or ARDS.
18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 14 , and a pharmaceutically acceptable excipient.
19 . The composition of claim 17 , wherein said compound is selected from the list consisting of a prostaglandin inhibitor, complement inhibitor, β-agonist, beta-2 agonist, granulocyte macrophage colony-stimulating factor, corticosteroid, N-acetylcysteine, statin, glucagon-like peptide-1 (7-36) amide (GLP-1), triggering receptor expressed on myeloid cells (TREM1) blocking peptide, 17-allylamino-17-demethoxygeldanamycin (17-AAG), antibody to tumor necrosis factor (TNF), recombinant interleukin (IL)-1 receptor antagonist, cisatracurium besilate, an antiviral, remdesivir, hydroxycholoroquine, chloroquine, and Angiotensin-Converting Enzyme (ACE) Inhibitor.
20 . The method of claim 14 , wherein said intracellular Calcium signaling inhibitor is a compound of chemical name N-(5-(7-chloro-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)-2,6-difluorobenzamide or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof.
Assignments (2)
SECURITY INTEREST
Recorded Mar 4, 2025
From: CALCIMEDICA, INC.
To: AVENUE CAPITAL MANAGEMENT II, L.P.
Reel/Frame 070394/0314 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Mar 13, 2023
From: STAUDERMAN, KENNETH A.; DUNN, MICHAEL; HEBBAR, SUDARSHAN; LEHENY, RACHEL
To: CALCIMEDICA, INC.
Reel/Frame 062964/0321 →
Continuity (3)
Provisional Application
63027092
· May 19, 2020
Provisional Application
62992826
· Mar 20, 2020
References Cited (287)
US 6348480B1
· Kubota et al.
· 2002
[cited by applicant]
US 6506747B1
· Betageri et al.
· 2003
[cited by applicant]
US 6958339B2
· Kubota et al.
· 2005
[cited by applicant]
US 7285554B2
· Kubota et al.
· 2007
[cited by applicant]
US 7709518B2
· Chen et al.
· 2010
[cited by applicant]
US 7816535B2
· Bohnert et al.
· 2010
[cited by applicant]
US 8030336B2
· Burns et al.
· 2011
[cited by applicant]
US 8546403B2
· Whitten et al.
· 2013
[cited by applicant]
US 8557861B2
· Chen
· 2013
[cited by applicant]
US 8754219B2
· Whitten et al.
· 2014
[cited by applicant]
US 8980629B2
· Whitten et al.
· 2015
[cited by applicant]
US 9120751B2
· Whitten et al.
· 2015
[cited by applicant]
US 9399638B2
· Irlapati et al.
· 2016
[cited by applicant]
US 9604978B2
· Chen et al.
· 2017
[cited by applicant]
US 9611233B2
· Yamada et al.
· 2017
[cited by applicant]
US 9856240B2
· Cao et al.
· 2018
[cited by applicant]
US 20010044445A1
· Bamaung et al.
· 2001
[cited by applicant]
US 20020034728A1
· Normant et al.
· 2002
[cited by applicant]
US 20030114353A1
· Parks et al.
· 2003
[cited by applicant]
US 20060030567A1
· Ehrenfreund et al.
· 2006
[cited by applicant]
US 20060067952A1
· Chen
· 2006
[cited by applicant]
US 20060100245A1
· Bakthavatchalam et al.
· 2006
[cited by applicant]
US 20060199845A1
· Sun et al.
· 2006
[cited by applicant]
US 20060235028A1
· Li et al.
· 2006
[cited by applicant]
US 20070031814A1
· Roos et al.
· 2007
[cited by applicant]
US 20070105867A1
· Chidambaram et al.
· 2007
[cited by applicant]
US 20070249050A1
· Chen et al.
· 2007
[cited by applicant]
US 20070249051A1
· Bohnert et al.
· 2007
[cited by applicant]
US 20070249609A1
· Chen et al.
· 2007
[cited by applicant]
US 20070249661A1
· Chen et al.
· 2007
[cited by applicant]
US 20070254363A1
· Chen et al.
· 2007
[cited by applicant]
US 20070254912A1
· Chen et al.
· 2007
[cited by applicant]
US 20070254925A1
· Vo et al.
· 2007
[cited by applicant]
US 20070254926A1
· Jiang et al.
· 2007
[cited by applicant]
US 20080064874A1
· Dunkel et al.
· 2008
[cited by applicant]
US 20080293092A1
· Stauderman et al.
· 2008
[cited by applicant]
US 20090311720A1
· Roos et al.
· 2009
[cited by applicant]
US 20100016598A1
· Valacchi et al.
· 2010
[cited by applicant]
US 20100041762A1
· Bohnert et al.
· 2010
[cited by applicant]
US 20100130510A1
· Chen et al.
· 2010
[cited by applicant]
US 20100130522A1
· Jiang et al.
· 2010
[cited by applicant]
US 20100152241A1
· Whitten
· 2010
[cited by applicant]
US 20100273744A1
· Gore et al.
· 2010
[cited by applicant]
US 20100286103A1
· Chen
· 2010
[cited by applicant]
US 20100292252A1
· Chen
· 2010
[cited by applicant]
US 20100311787A1
· Chen et al.
· 2010
[cited by applicant]
US 20110015184A1
· Bohnert et al.
· 2011
[cited by applicant]
US 20110052643A1
· Che et al.
· 2011
[cited by applicant]
US 20110105447A1
· Muthuppalaniappan et al.
· 2011
[cited by applicant]
US 20110112058A1
· Muthuppalaniappan et al.
· 2011
[cited by applicant]
US 20110130452A1
· Venkiteswaran et al.
· 2011
[cited by applicant]
US 20110230536A1
· Whitten et al.
· 2011
[cited by applicant]
US 20110263612A1
· Whitten et al.
· 2011
[cited by applicant]
US 20110305709A1
· Braun et al.
· 2011
[cited by applicant]
US 20120035237A1
· Coe et al.
· 2012
[cited by applicant]
US 20120053210A1
· Whitten et al.
· 2012
[cited by applicant]
US 20120316182A1
· Whitten et al.
· 2012
[cited by applicant]
US 20120316185A1
· Beattie et al.
· 2012
[cited by applicant]
US 20130252974A1
· Altenburger et al.
· 2013
[cited by applicant]
US 20140105984A1
· Ryde et al.
· 2014
[cited by applicant]
US 20140112978A1
· Su et al.
· 2014
[cited by applicant]
US 20140256771A1
· Cao et al.
· 2014
[cited by applicant]
US 20200101069A1
· Stauderman et al.
· 2020
[cited by applicant]
US 20200253966A1
· Stauderman et al.
· 2020
[cited by applicant]
US 20220056053A1
· Stauderman et al.
· 2022
[cited by applicant]
US 20230226058A1
· Stauderman et al.
· 2023
[cited by applicant]
US 20240058332A1
· Stauderman et al.
· 2024
[cited by applicant]
US 20240307384A1
· Velicelebi et al.
· 2024
[cited by applicant]
JP 2001080412A
· 2001
[cited by applicant]
JP 2001522834A
· 2001
[cited by applicant]
JP 2003527324A
· 2003
[cited by applicant]
JP 2007514720A
· 2007
[cited by applicant]
JP 2010522207A
· 2010
[cited by applicant]
JP 2014523911A
· 2014
[cited by applicant]
WO WO9806719A1
· 1998
[cited by applicant]
WO WO9924404A1
· 1999
[cited by applicant]
WO WO9951580A1
· 1999
[cited by applicant]
WO WO0114339A2
· 2001
[cited by applicant]
WO WO2004054977A1
· 2004
[cited by applicant]
WO WO2004056774A2
· 2004
[cited by applicant]
WO WO2005009539A2
· 2005
[cited by applicant]
WO WO2005009954A2
· 2005
[cited by applicant]
WO WO2005058871A1
· 2005
[cited by applicant]
WO WO2006006569A1
· 2006
[cited by applicant]
WO WO2006034402A2
· 2006
[cited by applicant]
WO WO2006081389A1
· 2006
[cited by applicant]
WO WO2006081391A2
· 2006
[cited by applicant]
WO WO2006083477A2
· 2006
[cited by applicant]
WO WO2006089177A2
· 2006
[cited by applicant]
WO WO2007052123A2
· 2007
[cited by applicant]
WO WO2007056341A1
· 2007
[cited by applicant]
WO WO2007059515A2
· 2007
[cited by applicant]
WO WO2007081804A2
· 2007
[cited by applicant]
WO WO2007087427A2
· 2007
[cited by applicant]
WO WO2007087429A2
· 2007
[cited by applicant]
WO WO2007093542A1
· 2007
[cited by applicant]
WO WO2007112093A2
· 2007
[cited by applicant]
WO WO2007120600A2
· 2007
[cited by applicant]
WO WO2008002576A2
· 2008
[cited by applicant]
WO WO2008063504A2
· 2008
[cited by applicant]
WO WO2008118754A2
· 2008
[cited by applicant]
WO WO2009020642A1
· 2009
[cited by applicant]
WO WO2009035818A1
· 2009
[cited by applicant]
WO WO2009111280A1
· 2009
[cited by applicant]
WO WO2010025295A2
· 2010
[cited by applicant]
WO WO2010027875A2
· 2010
[cited by applicant]
WO WO2010034011A2
· 2010
[cited by applicant]
WO WO2010122089A1
· 2010
[cited by applicant]
WO WO2010138539A2
· 2010
[cited by applicant]
WO WO2011034962A2
· 2011
[cited by applicant]
WO WO2011063277A1
· 2011
[cited by applicant]
WO WO2011139489A2
· 2011
[cited by applicant]
WO WO2011139765A2
· 2011
[cited by applicant]
WO WO2012027710A2
· 2012
[cited by applicant]
WO WO2012151355A1
· 2012
[cited by applicant]
WO WO2012170931A2
· 2012
[cited by applicant]
WO WO2012170951A2
· 2012
[cited by applicant]
WO WO2013059666A1
· 2013
[cited by applicant]
WO WO2013059677A1
· 2013
[cited by applicant]
WO WO2013164769A1
· 2013
[cited by applicant]
WO WO2014043715A1
· 2014
[cited by applicant]
WO WO2014059333A1
· 2014
[cited by applicant]
WO WO2014203217A1
· 2014
[cited by applicant]
WO WO2016138472A1
· 2016
[cited by applicant]
WO WO2017027400A1
· 2017
[cited by applicant]
WO WO2018140796A1
· 2018
[cited by applicant]
WO WO2020053834A1
· 2020
[cited by applicant]
WO WO2020072942A1
· 2020
[cited by applicant]
WO WO2021189013A1
· 2021
[cited by applicant]
WO WO2021236820A1
· 2021
[cited by applicant]
Berridge. Inositol trisphosphate and calcium signalling. Nature 361:315-325 (1993).
[cited by applicant]
Cho. Recent Advances in Oral Prodrug Discovery. Annual Reports in Medicinal Chemistry 41:395-407 (2006).
[cited by applicant]
Churchill et al. Imaging of intracellular calcium stores in single permeabilized lens cells. Am. J. Physiol. 276:C426-434 (1999).
[cited by applicant]
Dargie et al. Comparison of Ca2+ mobilizing activities of cyclic ADP-ribose and inositol trisphosphate. Cell Regul. 1:279-290 (1990).
[cited by applicant]
Fagan et al. Regulation of the Ca2+-inhibitable adenylyl cyclase type VI by capacitative Ca2+ entry requires localization in cholesterol-rich domains. J Biol Chem 275(34):26530-26537 (Aug. 25, 2000).
[cited by applicant]
Fedorak et al. A novel colon-specific steroid prodrug enhances sodium chloride absorption in rat colitis. Am. J. Physiol. 269:G210-218 (1995).
[cited by applicant]
Gandhirajan et al., Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest. 123:887-902 (2013).
[cited by applicant]
Gerasimenko et al. Inositol trisphosphate and cyclic ADP-ribose-mediated release of Ca2+ from single isolated pancreatic zymogen granules. Cell 84:473-480 (1996).
[cited by applicant]
Gromoda et al. Cyclic ADP-ribose and inositol 1,4,5-triphosphate mobilizes Ca2+ from distinct intracellular pools in permeabilized lacrimal acinar cells. FEBS Lett. 360:303-306 (1995).
[cited by applicant]
Guse et al. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 398:70-73 (1999).
[cited by applicant]
Hochhaus et al. A selective HPLC/RIA for dexamethasone and its prodrug dexamethasone-21-sulphobenzoate sodium in biological fluids. Biomed. Chrom. 6:283-286 (1992).
[cited by applicant]
Hofer et al. Free [Ca2+] dynamics measured in agonist-sensitive stores of single living intact cells: a new look at the refilling process. EMBO J. 17:1986-1995 (1998).
[cited by applicant]
Larsen et al. Prodrug forms for the sulfonamide group. I. Evaluation of N-acyl derivatives, N-sulfonylamindes, N-sulfonylsulfilimines and sulfonylureas as possible prodrug derivatives. Int. J. Pharmaceutics 37:87-95 (19…
[cited by applicant]
Larsen et al. Prodrug forms for the sulfonamide group. II. water-soluble amino acid derivatives of N-methylsulfonylamindes as possible prodrug derivatives. Int'l J of Pharmaceutics 47:103-110 (1988).
[cited by applicant]
Lewis. Calcium Signaling Mechanisms in T Lymphocytes. Annu Rev Immunol 19:497-521 (2001).
[cited by applicant]
Macian et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109(6):719-731 (Jun. 14, 2002).
[cited by applicant]
McLeod et al. A glucocorticoid prodrug facilitates normal mucosal function in rat colitis without adrenal suppression. Gastroenterol 106:405-413 (1994).
[cited by applicant]
Miller et al., Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial. Randomized Controlled Trial 24(1):502 (2020).
[cited by applicant]
Miller et al. Histone deacetylase inhibitors. Med. Chem. 46(24):5097-5116 (2003).
[cited by applicant]
Miyawaki et al. Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin. Nature 388(6645):882-887 (Aug. 28, 1997).
[cited by applicant]
Nogrady. Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pp. 388-392 (1985).
[cited by applicant]
Nunez et al. Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate. J Physiol. 571(Pt 1):57-73 (Feb. 15, 2006/ Epub Dec. 8, 2005).
[cited by applicant]
Parekh et al. Store Depletion and Calcium Influx. Physiol Rev 77(4):901-930 (1997).
[cited by applicant]
Parekh et al. Store-Operated Calcium Channels. Physiol Rev 85:757-810 (2005).
[cited by applicant]
PCT/US2021/023345 International Search Report and Written Opinion dated Jul. 15, 2021.
[cited by applicant]
Putney et al. A model for receptor-regulated calcium entry. Cell Calcium. 7(1):1-12 (1986).
[cited by applicant]
Putney et al. The signal for capacitative calcium entry. Cell 75(2):199-201 (1993).
[cited by applicant]
Rao et al. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 15:707-747 (1997).
[cited by applicant]
Rooseboom et al. Enzyme-catalyzed activation of anticancer prodrugs. Pharmacological Reviews 56:53-102 (2004).
[cited by applicant]
Rudensky et al. FOXP3 and NFAT: partners in tolerance. Cell 126(2):253-256 (2006).
[cited by applicant]
Sadikot et al. Nanomedicine for Treatment of Acute Lung Injury and Acute Respiratory Distress Syndrome. Biomed Hub 2(2):1-12 (2017).
[cited by applicant]
Saulnier et al. An Efficient Method for The Synthesis of Guanidino Prodrugs. Bioorg Med Chem Lett 4(16):1985-1990 (1994).
[cited by applicant]
Seeley et al. Calcium flux and endothelial dysfunction during acute lung injury: a STIMulating target for therapy. J Clin Invest 123(3):1015-8 (2013).
[cited by applicant]
Sheahan et al., Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against Mers-COV. Nat Commun 11(1):222 (2020).
[cited by applicant]
Silverman. Chapter 8: Prodrugs and Drug Delivery Systems. The Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc., San Diego (pp. 352-401) (1992).
[cited by applicant]
Sinkula et al. Rationale for design of biologically reversible drug derivatives: prodrugs. J. Pharm. Sci. 64:181-210 (1975).
[cited by applicant]
Streb et al. Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306:67-69 (1983).
[cited by applicant]
Waldron et al., The Orai Ca2+ channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis. J Physiol. 597(12):3085-3105 (2019).
[cited by applicant]
Wang et al., Inhibition of SOCs attenuates acute lung injury induced by severe acute pancreatitis in rats and PMVECs injury induced by lipopol-ysaccharide. Inflammation 39(3):1049-105 (2016).
[cited by applicant]
Wen et al. Orail inhibition prevents calcium toxicity and acute pancreatitis. Pancreatology 3.14 Supp 1:S100-S101 (2014).
[cited by applicant]
Winslow et al. Calcium Signalling in Lymphocytes. Current Opinion in Immunology 16:299-307 (2003).
[cited by applicant]
Wu et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126(2):375-387 (Jul. 28, 2006).
[cited by applicant]
Yu et al. Rapid turnover of calcium in the endoplasmic reticulum during signaling. Studies with cameleon calcium indicators. J. Biol. Chem. 275:23648-23653 (2000).
[cited by applicant]
Arthritis. http://en.wikipedia.org/wiki/Arthritis (1 pg.) (2014).
[cited by applicant]
Ashizawa. Optimization of salts/crystal form and crystallization technique. Pharm Tech Japan 18(10):81-96 (2002).
[cited by applicant]
Baba et al. Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. PNAS USA 103:16704-16709 (2006).
[cited by applicant]
Basile et al. T helper 17 cells in the pathophysiology of acute and chronic kidney disease. Kidney Res Clin Pract 40(1):12-28 (2021).
[cited by applicant]
Bauer, T. T. et al. Acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data. Clin Infect Dis. 43(6):748-756 (2006).
[cited by applicant]
Braga et al. Crystal polymorphism and multiple crystal forms. Molecular networks pp. 87-95 (2009).
[cited by applicant]
Brayer et al. Alleles from chromosomes 1 and 3 of NOD mice combine to influence Sjogren's syndrome-like autoimmune exocrinopathy. J. Rheumatol. 27:1896-1904 (2000).
[cited by applicant]
Caira. Crystalline Polymorphism of Organic Compounds. Topics in Current Chemistry. 198:163-208 (Jan. 1998).
[cited by applicant]
Chaplan, et al. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55-63 (1994).
[cited by applicant]
Chen et al., CAPlus Accession No. 2012:1630648 (2012).
[cited by applicant]
Colitis. http://www.healthline.com/health/ulterative-colitis-take-control-can-it-be-cured? (3 pgs) (2014).
[cited by applicant]
Dean et al. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. Current Pharmaceutical Design 6:110 (2000).
[cited by applicant]
Derler et al. The action of selective CRAC channel blockers is affected by the Orai pore geometry. Cell Calcium 53(2):139-151 (2013).
[cited by applicant]
European Medicines Agency. Public summary of opinion on orphan designation N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxo1-5-yl)pyrazin-2-y1)-2-fluoro-6-methylbenzamide for the treatment of acute pancreatitis. Committee …
[cited by applicant]
Evans. Synthesis of Radiolabelled Compounds. Journal of Radioanalytical and Nuclear Chemistry 64(1-2):9-32 (1981).
[cited by applicant]
Feske et al. A Mutation in Orai1 Causes Immune Deficiency by Abrogating CRAC Channel Function. Nature 441:179-185 (2006).
[cited by applicant]
Frick. The role of calcium in acute pancreatitis. Surgery 152(3 Suppl 1):S157-S163 (2012).
[cited by applicant]
Funaba et al. Degranulation in RBL-2H3 cells: regulation by calmodulin pathway. Cell Biol Int 27:879-885 (2003).
[cited by applicant]
Gerasimenko et al. Ca2+ release-activated Ca2+ channel blockade as a potential tool in antipancreatitis therapy. PNAS USA 110(32):13186-13191 (2013).
[cited by applicant]
Gerasimenko et al. Ca2+ signalling underlying pancreatitis. Cell Calcium 70:95-101 (2018).
[cited by applicant]
Gomez-Puerta et al. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Curr Top Med Chem. 13(6):760-773 (2013).
[cited by applicant]
Gompertz et al. Bedside index for severity in acute pancreatitis (BISAP) score as predictor of clinical outcome in acute pancreatitis: retrospective review of 128 patients. Rev Med Chil 140(8):977-983 (2012).
[cited by applicant]
Gorenjak. 4: Kidneys and Autoimmune Disease. Kidneys and Autoimmune disease—eJIFCC 20/01 http://www.ifcc.org (2009).
[cited by applicant]
Griffiths et al. Genetic analysis of collagen-induced arthritis in rats: a polygenic model for rheumatoid arthritis predicts a common framework of cross-species inflammatory/autoimmune disease loci. Immunol. Rev. 184:17…
[cited by applicant]
Guram et al. New catalysts for Suzuki-Miyaura coupling reactions of heteroatom-substituted heteroaryl chlorides. J Org Chem 72:5104-5112 (2007).
[cited by applicant]
Haider et al. Use of Calcium Channel Blockers is Associated with Mortality in Patients with Chronic Kidney Disease. Kidney Blood Press Res 40:630-637 (2015).
[cited by applicant]
Hilfiker et al. Relevance of solid-state properties for pharmaceutical products. Polymorphism: in the pharmaceutical industry pp. 1-19 (2006).
[cited by applicant]
Huang et al. STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels. Nature Cell Biology 8(9):1003-1010 (2006).
[cited by applicant]
Humbles et al. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. PNAS USA 99:1479-1484 (2002).
[cited by applicant]
Humphreys-Beher et al. New concepts for the development of autoimmune exocrinopathy derived from studies with the NOD mouse model. Arch. Oral Biol. 44( Suppl 1):S21-25 (1999).
[cited by applicant]
Jefferson et al. Experimental mesangial proliferative glomerulonephritis (the anti-Thy-1.1 model). J. Nephrol. 12:297-307 (1999).
[cited by applicant]
Kabalka et al., The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron 45(21):6601-6621 (1989).
[cited by applicant]
Karlsson et al. Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthiritis Phosphodiesterase 4 Inhibitors for the treatment of asthma. Exp. Opin. Their Patents. 7(9):989-1003 (1997).
[cited by applicant]
Kojima. Iyakuhin kaihatsu niokeru kesshosei sentaku no kouritsuka wo mezashite (Aiming at efficient selection of crystallinity in the development of pharmaceutical products). Journal of Pharmaceutical science and techno…
[cited by applicant]
Lian et al. ORAI1 mutations abolishing store-operated Ca 2+ entry cause anhidrotic ectodermal dysplasia with immunodeficiency. J Allergy Clin Immunol 142(4):1297-1310.e11 (2018).
[cited by applicant]
Liou et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15(13):1235-1241 (2005).
[cited by applicant]
Luik et al. The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J. Cell Biol. 174:815-825 (2006).
[cited by applicant]
Luo et al. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J. Neurosci 21:1868-1875 (2001).
[cited by applicant]
Manji et al. STIM1: a novel phosphoprotein located at the cell surface. Biochim Biophys Acta. 1481(1):147-155 (2000).
[cited by applicant]
Mercer et al. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. JBC 281:24979-24990 (2006).
[cited by applicant]
Michelucci et al. Role of STIM1/ORAI1-mediated store-operated Ca2+ entry in skeletal muscle physiology and disease. Cell Calcium 76:101-115 (2018).
[cited by applicant]
Millar et al. Functional expression of a cloned
[cited by applicant]
Miller et al. 353 An Open-Label, Dose-Response Study of CM4620-Injectable Emulsion in Emergency Department Patients With Acute Pancreatitis. Research Forum Abstract 74(4, Supplement):S138-S139 (2019).
[cited by applicant]
Multiple Sclerosis Prevention. Retrieved from http://www.webmd.com/multiple-sclerosis/tc/multiple-sclerosis-ms-prevention (3 pgs.) (2017).
[cited by applicant]
Multiple Sclerosis Treatment. Retrieved from http://www.webmd.com/multiple-sclerosis/tc/multiple-sclerosis-ms-medications#1 (4 pgs) (2017).
[cited by applicant]
Papachristou et al. Comparison of Bisap, Ranson's, Apache-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol. 105(2):435-441 (2010).
[cited by applicant]
Patani et al., Bioisosterism: A Rational Approach In Drug Design. Chemical Reviews. American Chemical Society 96:3147-3176 (1996).
[cited by applicant]
Patterson et al. Phospholipase C-γ is Required for Agonist-Induced Ca2+ Entry. Cell 111(4):529-541 (2002).
[cited by applicant]
PCT/US2011/031992 International Search Report and Written Opinion dated Dec. 7, 2011.
[cited by applicant]
PCT/US2016/019924 International Search Report and Written Opinion dated Jul. 8, 2016.
[cited by applicant]
PCT/US2016/045846 International Search Report and Written Opinion dated Oct. 24, 2016.
[cited by applicant]
PCT/US2018/015555 International Search Report and Written Opinion dated Apr. 4, 2018.
[cited by applicant]
PCT/US2021/033237 International Search Report and Written Opinion dated Jul. 30, 2021.
[cited by applicant]
Petersen. Can specific calcium channel blockade be the basis for a drug-based treatment of acute pancreatitis? Expert Reviews 8(4):339-341 (2014).
[cited by applicant]
Prakriya et al. Store-Operated Calcium Channels. Physiol Rev 95:1383-1436 (2015).
[cited by applicant]
Prakriya et al. Store-operated calcium channels: properties, functions and the search for a molecular mechanism. Molecular and Cellular Insights into lon Channel Biology 32:121-140 (2004).
[cited by applicant]
RN1269124-20-0, registry database compound, Mar. 21, 2011.
[cited by applicant]
Roos et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol 169(3):435-445 (2005).
[cited by applicant]
Spassova et al. STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. PNAS USA103:4040-4045 (2006).
[cited by applicant]
Stathopulos et al. Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: An initiation mechanism for capacitive Ca2+ entry. J. Biol. Chem. 281:35855-35862 (2006).
[cited by applicant]
Takata. API form screening and selection in drug discovery stage. Pharm Stage 6(10):20-25 (2007).
[cited by applicant]
Takizawa et al. Caplus AN 2006:50793 (WO2006006569) (2 pgs) (2006).
[cited by applicant]
Trevilyan et al. Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. J Biol Chem. 276(51):48118-48126 (2001).
[cited by applicant]
U.S. Appl. No. 13/085,324 Office Action dated Feb. 8, 2013.
[cited by applicant]
U.S. Appl. No. 13/969,401 Office Action dated Dec. 10, 2014.
[cited by applicant]
U.S. Appl. No. 13/969,401 Office Action dated Jul. 8, 2014.
[cited by applicant]
U.S. Appl. No. 13/969,401 Office Action dated Mar. 17, 2014.
[cited by applicant]
U.S. Appl. No. 13/975,238 Office Action dated Jan. 27, 2014.
[cited by applicant]
U.S. Appl. No. 13/975,238 Office Action dated Jun. 9, 2014.
[cited by applicant]
U.S. Appl. No. 14/805,292 Office Action dated Aug. 21, 2017.
[cited by applicant]
U.S. Appl. No. 14/805,292 Office Action dated Feb. 6, 2017.
[cited by applicant]
U.S. Appl. No. 14/805,292 Office Action dated Mar. 30, 2018.
[cited by applicant]
U.S. Appl. No. 14/805,292 Office Action dated Oct. 18, 2018.
[cited by applicant]
U.S. Appl. No. 15/553,531 Office Action dated Apr. 6, 2020.
[cited by applicant]
U.S. Appl. No. 15/553,531 Office Action dated Aug. 13, 2019.
[cited by applicant]
U.S. Appl. No. 15/553,531 Office Action dated Dec. 9, 2020.
[cited by applicant]
U.S. Appl. No. 15/553,531 Office Action dated Jun. 14, 2021.
[cited by applicant]
U.S. Appl. No. 15/751,098 Office Action dated Nov. 26, 2018.
[cited by applicant]
U.S. Appl. No. 16/481,380 Office Action dated Jan. 14, 2022.
[cited by applicant]
U.S. Appl. No. 16/481,380 Office Action dated May 23, 2023.
[cited by applicant]
U.S. Appl. No. 16/481,380 Office Action dated Sep. 22, 2022.
[cited by applicant]
U.S. Appl. No. 16/535,968 Office Action dated Apr. 13, 2022.
[cited by applicant]
U.S. Appl. No. 16/535,968 Office Action dated Mar. 30, 2021.
[cited by applicant]
U.S. Appl. No. 16/535,968 Office Action dated Oct. 7, 2021.
[cited by applicant]
U.S. Appl. No. 16/653,475 Office Action dated Apr. 17, 2023.
[cited by applicant]
U.S. Appl. No. 16/653,475 Office Action dated Jun. 7, 2021.
[cited by applicant]
U.S. Appl. No. 16/653,475 Office Action dated Nov. 19, 2021.
[cited by applicant]
U.S. Appl. No. 16/653,475 Office Action dated Sep. 15, 2022.
[cited by applicant]
U.S. Appl. No. 16/988,508 Office Action dated Aug. 25, 2020.
[cited by applicant]
U.S. Appl. No. 17/203,547 Office Action dated Dec. 28, 2022.
[cited by applicant]
U.S. Appl. No. 17/472,422 Office Action dated Jan. 25, 2022.
[cited by applicant]
Vig et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312(5777):1220-1223 (2006).
[cited by applicant]
Vig et al. CRACM1 Multimers Form the Ion-Selective Pore of the CRAC Channel. Current Biology 16:2073-2079 (2006).
[cited by applicant]
Voronina et al. The role of Ca2+ influx in endocytic vacuole formation in pancreatic acinar cells. Biochemical J 465(3):405-412 (2015).
[cited by applicant]
Williams et al. Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem. J. 357:673-685 (2001).
[cited by applicant]
Wu et al. Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174(6):803-813 (2006).
[cited by applicant]
Wu et al. The early prediction of mortality in acute pancreatitis: a large population-based study. Gut 57(12):1698-1703 (2008).
[cited by applicant]
Xu et al. Aggregation of STIM1 underneath the plasma membrane induces clustering of Orai1. Biochem. Biophys. Res. Commun. 350:969-976 (2006).
[cited by applicant]
Yagodin et al. Functional characterization of thapsigargin and agonist-insensitive acidic Ca2+ stores in
[cited by applicant]
Yagodin et al. Thapsigargin and receptor-mediated activation of
[cited by applicant]
Yeromin et al. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443:226-229 (2006).
[cited by applicant]
Zhang et al. Genome Wide RNAi Screen of Ca2+ influx identifies Genes that Regulate Ca2+ Channel Activity. PNAS USA 103(4):9357-9362 (2006).
[cited by applicant]
Zhang et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437(7060):902-905 (2005).
[cited by applicant]
Tang, S. et al. Calcium Release-Activated Calcium Channel Inhibitor, BTP2, Attenuates Ventilator-Induced Lung Injury in Rats. American Journal of Respiratory and Critical Care Medicine 199:A1159 (2019).
[cited by applicant]